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Nuclear factor-kappaB activation leads to down-regulation of fatty acid oxidation during cardiac hypertrophy.

Authors: Planavila, A  Laguna, JC  Vazquez-Carrera, M 
Citation: Planavila A, etal., J Biol Chem. 2005 Apr 29;280(17):17464-71. Epub 2005 Feb 22.
Pubmed: (View Article at PubMed) PMID:15728586
DOI: Full-text: DOI:10.1074/jbc.M414220200

Little is known about the mechanisms responsible for the fall in fatty acid oxidation during the development of cardiac hypertrophy. We focused on the effects of nuclear factor (NF)-kappaB activation during cardiac hypertrophy on the activity of peroxisome proliferator-activated receptor (PPAR) beta/delta, which is the predominant PPAR subtype in cardiac cells and plays a prominent role in the regulation of cardiac lipid metabolism. Phenylephrine-induced cardiac hypertrophy in neonatal rat cardiomyocytes caused a reduction in the expression of pyruvate dehydrogenase kinase 4 (Pdk4), a target gene of PPARbeta/delta involved in fatty acid utilization, and a fall in palmitate oxidation that was reversed by NF-kappaB inhibitors. Lipopolysaccharide stimulation of NF-kappaB in embryonic rat heart-derived H9c2 myotubes, which only express PPARbeta/delta, caused both a reduction in Pdk4 expression and DNA binding activity of PPARbeta/delta to its response element, effects that were reversed by NF-kappaB inhibitors. Coimmunoprecipitation studies demonstrated that lipopolysaccharide strongly stimulated the physical interaction between the p65 subunit of NF-kappaB and PPARbeta/delta, providing an explanation for the reduced activity of PPARbeta/delta. Finally, we assessed whether this mechanism was present in vivo in pressure overload-induced cardiac hypertrophy. In hypertrophied hearts of banded rats the reduction in the expression of Pdk4 was accompanied by activation of NF-kappaB and enhanced interaction between p65 and PPARbeta/delta. These results indicate that NF-kappaB activation during cardiac hypertrophy down-regulates PPARbeta/delta activity, leading to a fall in fatty acid oxidation, through a mechanism that involves enhanced protein-protein interaction between the p65 subunit of NF-kappaB and PPARbeta/delta.


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CRRD Object Information
CRRD ID: 1580656
Created: 2006-08-21
Species: All species
Last Modified: 2006-08-21
Status: ACTIVE


RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.